Purification of vitamin D3

ABSTRACT

Crude vitamin D 3  is purified by reaction with a dienophile followed by short-path distillation.

The present invention relates to a process for the purification of crudevitamin D₃ by combining a conventional treatment with a dienophile and ashort-path distillation.

When 7-dehydrocholesterol or ergosterol is irradiated and the unreactedstarting material is separated off, vitamin D₂ resin or vitamin D₃resin, which has a vitamin content of about 63%, is obtained (TheVitamins, Vol. III, page 203, 1971, W. H. Sebrell, Jr. and R. S. Harrised.). The vitamin D content is the sum of the contents of vitamin D andprovitamin D. The vitamin D resin also contains some isomers, such astachysterol, lumisterol and ergosterol or 7-dehydrocholesterol.

There has been no lack of attempts to separate vitamin D₂ and vitamin D₃from the by-products formed during irradiation. For example, the contentof vitamin D₃ can be increased by forming crystalline adducts with7-dehydrocholesterol (FR No. 1,378,121 and U.S. Pat. No. 3,367,950) orcholesterol (U.S. Pat. No. 2,264,320). Crystalline esters of vitamin D₂or D₃, e.g. the dinitrobenzoates, can also be prepared. Such esters canbe purified by recrystallization, and then hydrolyzed to give highlyconcentrated vitamin D preparations. Finally, crude vitamin D has alsobeen reacted with maleic anhydride and citraconic anhydride with theobject of converting the tachysterol selectively to Diels-Alder adducts,which can then be extracted with alkali (GB Nos. 370,743 and 491,653).

However, all of the conventional methods are technically very involvedand entail substantial losses of the expensive vitamins, and some ofthem produce negligible purification effects. In particular, thepurification method which employs maleic anhydride or citraconicanhydride has not become an established one because, apart fromtachysterol, vitamin D₂ and vitamin D₃ also react with these dienophilesand hence undergo decomposition. Moreover, traces of acid, which canreadily form from the anhydrides, catalyze the decomposition of thevitamins.

It is an object of the present invention to provide a process whichpermits purification of the crude vitamin D₃ with very little loss ofvitamin activity.

We have found that this object is achieved, and that, surprisingly, asignificant part of the impurities can be removed from vitamin D₂ or D₃resin without loss of vitamin, if the crude resin is reacted with adienophile in the presence or absence of a solvent, and the product isthen subjected to a short-path distillation under reduced pressure.

Short-path distillation, also known as molecular distillation, is amethod in which the material being distilled traverses a short distancein passing from a heated surface to a cooled surface; in the presentcase, the residence time on the heated surface should be very short,e.g. less than 10 minutes at 190° C.

Suitable apparatuses are described in, for example, The Application ofMolecular Distillation by Hollo, Kurucz and Borodi, published byAkademiai Kiado, Budapest 1971. Particularly suitable apparatuses arethose in which thin films are produced on the evaporator surface bymeans of gravity or mechanical distribution. Specific examples arefalling-film evaporators with or without wipers, the distance betweenthe heated surface and the cooled surface advantageously being no longerthan the free path of the molecules under the chosen temperature andpressure conditions. As a rule, this is from a few millimeters to a fewcentimeters, for example less than 5, preferably from 0.3 to 3,centimeters.

Suitable dienophiles are any unsaturated compounds which readily undergoDiels-Alder addition reactions with electron-rich dienes, such ascyclopentadiene, butadiene or 9,10-dimethylanthracene, with the provisothat they do not contain any strongly acidic functional groups or anystructural elements, e.g. acid chloride or anhydride groups, which canreact with alcohols or water to form strong acids. Dienophiles aredescribed in detail in, for example, H. Wollweber,Diels-Alder-Reaktionen, Georg Thieme Verlag, Stuttgart, 1972, pages54-65 and 185-212, and in H. Sauer, Angew. Chemie 79 (1967) 76.

Accordingly, specific examples are p-benzoquinone, maleic acidN-methylimide, maleic acid N-butylimide, maleic acid N-phenylimide,esters of fumaric acid with lower aliphatic alcohols, esters of maleicacid with lower aliphatic alcohols, acrylonitrile, methacrylonitrile,1,2-dicyanoethylene, 1,1-dicyanoethylene, esters of acrylic acid withlower aliphatic alcohols or diols, esters of methacrylic acid with loweraliphatic alcohols, esters of acetylenedicarboxylic acid with loweraliphatic alcohols, esters of propiolic acid with lower aliphaticalcohols, unsaturated sulfones, such as 1,2-diphenylsulfonylethylene,unsaturated ketones, such as 1,2-dibenzoylethylene, unsaturated nitrocompounds, such as β-nitrostyrene, esters of azodicarboxylic acids withlower aliphatic alcohols, electron-deficient aromatic azo compounds,such as p,p'-dinitroazobenzene, and nitroso compounds, such asnitrosobenzene.

In order to facilitate the subsequent short-path distillation, it isadvantageous to choose dienophiles which are substantially more volatilethan vitamin D. Thus, residual unreacted dienophile remaining after thereaction with vitamin D resin can be distilled off before the short-pathdistillation of the vitamin. Particularly suitable dienophiles aremethyl acrylate, ethyl acrylate, n-butyl acrylate, butanedioldiacrylate, p-benzoquinone and N-methylmaleimide.

As a rule, from 0.05 to 5, preferably from 0.1 to 0.5 mole of dienophileare used per mole of the vitamin D resin being purified. The reactionwith the dienophile can be carried out in the presence of any desiredorganic solvent which is inert under the reaction conditions, e.g.ether, toluene or heptane, or in the absence of a solvent. If it isintended to use a carrier, e.g. peanut oil, for the short-pathdistillation, it is advantageous to carry out the reaction with thedienophile in the presence of the carrier oil, since this reduces thehigh viscosity of vitamin D₃ resin and accordingly facilitates mixing ofthe reactants.

The reaction with the dienophile can be carried out at from 0° to 150°C., preferably from 20° to 80° C. Depending on the reactivity of thedienophile, a reaction time of from a few minutes to about 20 hours isrequired. Excess unreacted dienophile which still remains after thereaction is distilled off under from 0.001 to 1,000 mbar and at from 20°to 120° C.

The vitamin D which has been freed from excess dienophile is finallydistilled over at from 130° to 200° C. and under from 0.001 to 0.1 mbarin a continuous short-path still in which the distance between theevaporation surface and the condensation surface should be no more than5 cm. The short-path distillation can be carried out using a sparinglyvolatile carrier oil, for example a high-boiling paraffin or peanut oil.The temperature, the pressure and the feed are advantageously set sothat from 70 to 95% of the vitamin distills over. Depending on thepurity of the crude vitamin D resin used, the distillate contains from65 to 78% of vitamin D. Thus, as a result of the novel process, thevitamin content is increased by 5-15% (absolute).

The bottom product of the short-path distillation can be recycled asmany as five times. The total loss of desired product is then less than3%.

EXAMPLE 1

0.4 g of p-benzoquinone and 19.3 g of vitamin D₃ resin, which contained11.7% of provitamin D₃ and 49.0% of vitamin D₃, were dissolved in 100 mlof n-heptane. The solution was left to stand for 6 hours at 25° C.,after which 19.3 g of peanut oil were added and the heptane wasdistilled off under 30 mbar, the bath temperature being increased to 80°C. The distillation residue was then metered continuously into ashort-path still in the course of 84 minutes. The vitamin D₃ distilledover a distance of 1.3 cm from the evaporator surface to the condensersurface, distillation taking place at 150° C./0.01 mbar. 12.8 g ofdistillate containing 15.9% of provitamin D₃ and 57.1% of vitamin D₃were obtained. The bottom product of the distillation comprised 26 g ofan oil which contained 1.8% of provitamin D₃ and 7.0% of vitamin D₃.

EXAMPLE 2

1.6 g of p-benzoquinone and 85.4 g of vitamin D₃ resin, which contained12.8% of provitamin D₃ and 51.4% of vitamin D₃, were mixed with 85.4 gof peanut oil at 60° C. The mixture was kept at 25° C. for 200 minutesand was then subjected to a continuous short-path distillation under theconditions described in Example 1. 69.8 g of distillate containing 13.7%of provitamin D₃ and 59.8% of vitamin D₃ were obtained. 101 g of bottomproduct, containing 0.5% of provitamin D₃ and 2.3% of vitamin D₃,resulted.

EXAMPLE 3

4.0 g of methyl acrylate and 50 g of vitamin D₃ resin, which contained9.8% of provitamin D₃ and 50.4% of vitamin D₃, were mixed with 50 g ofpeanut oil at 60° C. The mixture was heated at 60° C. for 2 hours, afterwhich traces of unreacted acrylate were evaporated at 80° C./30 mbar,and the remaining oil was then subjected to a continuous short-pathdistillation as described in Example 1. 32.1 g of distillate containing11.7% of provitamin D₃ and 63.2% of vitamin D₃ were obtained. 71.0 g ofbottom product, containing 1.8% of provitamin D₃ and 6.6% of vitamin D₃resulted.

EXAMPLE 4

1.2 g of n-butyl acrylate and 19.9 g of vitamin D₃ resin, containing7.2% of provitamin D₃ and 58.2% of vitamin D₃, were mixed with 19.9 g ofpeanut oil at 60° C. The mixture was heated at 50° C. for 2 hours afterwhich traces of unreacted acrylate were evaporated at 80° C./30 mbar,and the remaining oil was then subjected to a continuous short-pathdistillation as described in Example 1. 15.0 g of distillate containing10.8% of provitamin D₃ and 62.7% of vitamin D₃ were obtained. 25.5 g ofbottom product, containing 2.0% of provitamin D₃ and 5.8% of vitamin D₃,resulted.

EXAMPLE 5

1.0 g of N-methylmaleimide and 20 g of vitamin D₃ resin, containing11.9% of provitamin D₃ and 48.8% of vitamin D₃, were dissolved in 100 mlof methyl tert-butyl ether. The mixture was left to stand at 25° C. for20 hours, after which 20 g of peanut oil were added and the solvent wasdistilled off under 30 mbar, the bath temperature being increased to 80°C. The remaining oil was then subjected to a continuous short-pathdistillation as described in Example 1. 16 g of distillate containing9.7% of provitamin D₃ and 63.4% of vitamin D₃ were obtained. 25 g ofdistillation residue, containing 0.4% of provitamin D₃ and 1.2% ofvitamin D₃, resulted.

EXAMPLE 6

1.6 g of N-phenylmaleimide and 20 g of vitamin D₃ resin, containing11.9% of provitamin D₃ and 48.8% of vitamin D₃, were dissolved in 100 mlof methyl tert-butyl ether. Using the procedure described in Example 5,15.5 g of distillate containing 10.2% of provitamin D₃ and 61.4% ofvitamin D₃ were obtained. 26 g of distillation residue, containing 0.5%of provitamin D₃ and 3.3% of vitamin D₃, resulted.

EXAMPLE 7

4.8 g of methyl acrylate and 50 g of vitamin D₂ resin, containing 8.7%of provitamin D₂ and 54.2% of vitamin D₂, were dissolved in 50 g ofpeanut oil at 60° C. The mixture was heated at 60° C. for 2 hours, afterwhich traces of unreacted acrylate were evaporated at 80° C./30 mbar,and the remaining oil was then subjected to a continuous short-pathdistillation as described in Example 1. 35.2 g of distillate containing9.7% of provitamin D₂ and 88.1% of vitamin D₂ were obtained. 68 g ofbottom product, containing 1.1% of provitamin D₂ and 4.8% of vitamin D₂,resulted.

EXAMPLE 8

60 g of methyl acrylate and 1,000 g of vitamin D₃ resin, containing11.2% of provitamin D₃ and 52.4% of vitamin D₃, were mixed with 1,000 gof peanut oil at 60° C. The mixture was heated at 60° C. for 2 hours,after which traces of unreacted acrylate were evaporated at 80° C./30mbar, and the remaining oil was then metered continuously into ashort-path still in the course of 60 minutes. The vitamin D₃ distilledover a distance of 2.5 cm from the evaporator surface to the condensersurface, distillation taking place at 188° C./0.01 mbar. 768 g ofdistillate containing 11.8% of provitamin D₃ and 64.0% of vitamin D₃were obtained. 1,282 g of distillation residue, containing 0.5% ofprovitamin D₃ and 3.7% of vitamin D₃, resulted.

The bottom product from the distillation was mixed with 1,282 g ofvitamin D₃ resin, containing 11.2% of provitamin D₃ and 52.4% of vitaminD₃, and with 77 g of methyl acrylate at 60° C., and the resultingmixture was processed as described above. 1,090 g of distillatecontaining 9.9% of provitamin D₃ and 62.1% of vitamin D₃ were obtained.1,540 g of bottom product, containing 0.8% of provitamin D₃ and 4.6% ofvitamin D₃, were obtained.

The bottom product from the distillation was once again mixed with 1,540g of vitamin D₃ resin, containing 11.2% of provitamin D₃ and 52.4% ofvitamin D₃, and with 92 g of methyl acrylate at 60° C., and theresulting mixture was processed as described above. 1,335 g ofdistillate containing 10.1% of provitamin D₃ and 60.7% of vitamin D₃were obtained. 1,820 g of bottom product, containing 0.7% of provitaminD₃ and 5.3% of vitamin D₃, resulted.

EXAMPLE 9

2.4 g of butanediol diacrylate and 36.3 g of vitamin D₃ resin,containing 11.2% of provitamin D₃ and 56.3% of vitamin D₃, were mixedwith 36.3 g of peanut oil at 60° C. The mixture was heated at 60° C. for4 hours, after which it was subjected to a continuous short-pathdistillation as described in Example 1. 29.2 g of distillate containing16.7% of provitamin D₃ and 58.1% of vitamin D₃ were obtained. 45.6 g ofdistillation residue, containing 1.1% of provitamin D₃ and 4.8% ofvitamin D₃, resulted.

EXAMPLE 10

1.8 g of acrylonitrile and 37.8 g of vitamin D₃ resin, containing 11.2%of provitamin D₃ and 56.3% of vitamin D₃, were mixed with 37.8 g ofpeanut oil at 60° C. The mixture was heated at 60° C. for 6 hours, afterwhich traces of unreacted acrylonitrile were evaporated at 80° C./30mbar, and the remaining oil was then subjected to a continuousshort-path distillation as described in Example 1. 29.3 g of distillatecontaining 14.5% of provitamin D₃ and 59.4% of vitamin D₃ were obtained.46.8 g of distillation residue, containing 1.2% of provitamin D₃ and8.0% of vitamin D₃, resulted.

We claim:
 1. A process for the purification of vitamin D₃, whereinvitamin D₃ resin is reacted with a dienophile, and the product is thensubjected to a short-path distillation.
 2. A process as claimed in claim1, wherein vitamin D₃ resin is reacted with a dienophile which does notcontain any strongly acidic groups or functional groups which can reactwith alcohol or water to form strongly acidic groups.
 3. A process asclaimed in claim 1, wherein the vitamin D₃ resin used has been obtainedby irradiating 7-dehydrocholesterol or ergosterol.
 4. A process asclaimed in claim 1, wherein the reaction with the dienophile is carriedout in a solvent.
 5. A process as claimed in claim 1, wherein thevitamin D₃ resin is reacted with a dienophile which is substantiallymore volatile than vitamin D₃.